GE Port J Gastroenterol. 2015;22(5):213---220
www.elsevier.pt/ge
REVIEW ARTICLE
Neuroendocrine Rectal Tumors: Main Features and Management ¸as, Isabel Pedroto Ângela Rodrigues ∗ , Fernando Castro-Poc Gastroenterology Department, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal Received 24 March 2015; accepted 29 April 2015 Available online 2 July 2015
KEYWORDS Neuroendocrine Tumors; Rectal Neoplasms
PALAVRAS-CHAVE Tumores Neuroendócrinos; Neoplasias do Reto
∗
Abstract The incidence of neuroendocrine tumors of the rectum has been increasing in the last decades, partly due to improved investigation. They are mostly well-differentiated small tumors with a rather good overall prognosis. In the last few years, some aspects of neuroendocrine tumors have been evolving. In 2010, the World Health Organization proposed a new classification, indicating that these tumors, as a category, should be considered malignant. Afterwards the European Neuroendocrine Tumor Society published their guidelines for the management of colorectal neoplasms. Treatment algorithm is mainly based on tumor size and grading and, in general, well-differentiated rectal tumors 20%
a
Per 10 high-power fields.
neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma. NETs are well-differentiated neuroendocrine neoplasms, with low cellular atypia and proliferative activity and comprises grade G1 or G2 tumors. NECs are a poorly differentiated neuroendocrine neoplasm, showing marked cellular atypia and high proliferative activity. NECs are grade G3 tumors and two categories are recognized: large cell NEC and small cell NEC.4,5 Jernman et al6 demonstrated that this new WHO classification predicted the metastatic potentional of rectal NETs better than the previous 2000 classification, since G1 NETs had an indolent clinical course and G2 NETs often metastasize. Yamaguchi et al7 also concluded that the classification of gastrointestinal NETs into G1 and G2 based on Ki-67 index was appropriated to predict metastases and recurrences; for Salama et al8 Ki-67 appears as a reliable and reproducible marker for the grading of NETs and more superior than mitotic rate. The American Joint Cancer Commission published, in 2010, a tumor---node---metastasis (TNM) classification system for colorectal NETs similar to the one previous proposed by the European Neuroendocrine Tumor Society (Table 2).9 In order to assess the relevance of the TNM classification system, Jann et al10 conducted a retrospective study with midgut and hindgut NETs that confirmed the prognostic relevance and applicability of the classification. In 2012, the European Neuroendocrine Tumor Society (ENETS) released guidelines for the management of patients with colorectal neuroendocrine neoplasms, to reflect the new relevant data on this matter, including the WHO classification.5
3. Epidemiology Data from the Surveillance, Epidemiology and End Results (SEER) suggests that the incidence of rectal NETs have been increasing over the last decades; rectal NETs represented 29% of all GEP-NETs in the latest report, establishing the rectum as the most common location, slightly above the small intestine.11 In Europe, as indicated by an English12 and an Austrian13 studies, the rectum was the fifth and fourth most common location with a frequency of 8% and 14%, respectively. In Asia, rectal NETs take on special relevance, representing 56% of all GEP-NETs in Ito et al14 study. In Modlin et al15 report, rectal NETs also appear to
Neuroendocrine Rectal Tumors
215
Table 2 American Joint Cancer Commission 2010 TNM classification. T (primary tumor) Tx Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor invades lamina propria or submucosa and size ≤2 cm T1a Tumor size 2 cm with invasion of lamina propria or submucosa T3 Tumor invades through muscular propria into subserosa or into nonperitonealized pericolic or perirectal tissue T4 Tumor invades peritoneum or other organs N (Regional Lymph nodes) Nx Regional lymph nodes cannot be assessed N1 No regional lymph node metastases N2 Regional lymph node metastases M (Distant metastases) M0 No distant metastases M1 Distant metastases Stage I IIA IIB IIIA IIIB IV
T1N0M0 T2N0M0 T3N0M0 T4N0M0 AnyTN1M0 AnyTAnyNM1
be over-represented among the Asian populations within the United States. These data suggests that there are likely genetic pre-disposing factors, although some differences may also be attributable to higher colonoscopy screening rates and better reporting of polyps removed at endoscopy.3 Rectal NETs may have a slight male preponderance16,17 and the diagnosis is usually made in the sixth decade of life.16---18
Figure 1
Submucosal tumor in the middle rectum.
Lymph node and distant metastasis are found in about 8% and 4% of patients, respectively.20 Rectal NETs have a good overall prognosis with a 5-year survival rate of 75.2---88.3%.15 Disease stage is the main prognostic factor of rectal NETs. The 5-year overall survival rates reported are 94---100, 54---74 and 15---37% for patients with localized, nodal positive and metastatic rectal NETs, respectively.23 Risk factors for metastatic disease include tumor size, muscularis propria invasion, proliferation index, lymphovascular and perineural invasion.5,20,23 Yoon et al.16 described distant metastasis rates for tumors ≤1 cm, >1 to ≤2 cm, and >2 cm of 1.7, 15 and 50%, respectively. Weinstock et al22 reported 5-years survival rates of 87.7, 47.6 and 33.3% for patients with G1, G2 e G3 tumors, respectively.
5. Diagnosis and staging 5.1. Colonoscopy
4. Clinical characteristics, prognosis Most patients are asymptomatic and diagnosis is made upon routine lower endoscopy or for investigation of unrelated symptoms. In symptomatic patients, the most frequent symptoms are rectal bleeding, pain, constipation and tenesmus.3,16 Carcinoid syndrome is very rare as the tumors themselves rarely produce serotonin.5 The majority of rectal NETs are small size lesions; in a recent systematic review 79% of tumors were less than 1 cm and only 5% were greater than 2 cm.19 Kasuga et al20 reported a mean tumor size of 7.1 mm in their series. Most lesions are found in the midrectum as suggested by Kim et al21 study, in which 74.8% of tumors were found between 5 and 9.9 cm of the anal verge. Most rectal NETs (89%) are limited to the submucosa layer20 and are low grade tumors; Weinstock et al22 reported that G1 tumors accounted for 88.1, G2 for 8.2 and G3 for 3.5% of rectal neoplasms in their series.
Rectal NETs appear usually as small, sessile, submucosal tumors covered with yellow discolored mucosa.19 Atypical endoscopic features such as unusual tumor shape (semipedunculated and ulcerofungating), color (hyperemia) and surface change (depression, erosion, and ulceration) can be associated with metastasis.21 A full colonoscopy is recommended to exclude concomitant colonic disease and the possibility of synchronous carcinoma5 (Figs. 1 and 2).
5.2. Rectal ultrasound Rectal ultrasound (RUS) can accurately assess tumor size, depth of invasion and presence of pararectal lymph node metastases, which is particularly important to determine the adequate treatment modality.5 Kobayashi et al performed ultrasonographic evaluation with echocolonoscopes in 21 lesions and ultrasonic probes in 32 lesions. Rectal
216
Figure 2
Â. Rodrigues et al.
Submucosal tumor with yellow discolored mucosa.
NETs appeared as well-demarcated, homogenous, isoechoic or hypoechoic lesions and the depth of invasion was correctly identified in all lesions (submucosal in 49/52 lesions). RUS could accurately diagnose the invasion depth of lesions as small as 2 mm in diameter.24 High frequency ultrasound probes proved to be especially useful in assessing invasion of small lesions limited to the mucosa or submucosa25 and therefore can be particularly adequate for evaluating the depth of invasion in neuroendocrine rectal tumors. Another two studies found an accuracy of 91 and 100% for determination of tumor invasion with RUS.26,27 According to ENETS recommendation RUS should be performed prior to treatment to determine tumor invasion5 (Figs. 3 and 4).
Figure 4
Hypoechoic lesion on the submucosal layer.
5.3. Computed tomography and magnetic resonance In rectal NETs, the role of computed tomography (CT) is not to detect the primary tumor nor to appreciate its invasion of the rectal wall, but to detect regional and distant metastases. CT has a reported mean detection rate for liver metastasis in neuroendocrine tumors of 81%. The CT appearance of NET lymph node metastases is similar to those from other malignant tumors, although a marked contrast enhancement is frequent.2 Magnetic resonance imaging (MRI) is superior for determining liver metastases and can be used where there is uncertainty over the nature of lesions identified on CT.3,5 The ENETS consensus recommend CT/MRI for patients with tumors >10 mm in size and when residual and metastatic disease is suspected.5 In the NANETS guidelines it is stated that for tumors smaller than 2 cm and confined to the mucosa or submucosa, these studies are not routinely recommended.9
5.4. Scintigraphic scanning (Octreoscan)
Figure 3
Hypoechoic lesion on the muscularis mucosa layer.
Radiolabelled somatostatin analogs are used to detect somatostatin receptor positive tissue. The detection of primary tumor in the rectum NETs can be difficult because of greater background activity. In addition, some tumors may not express somatostatin receptors, particularly higher grade NETS, and so the presence of metastatic disease is better evaluated by other methods such as CT. In the presence of metastatic disease, this method can be useful to determine somatostatin receptor expression which may have impact in selecting some therapies.3,5
Neuroendocrine Rectal Tumors
5.5. Positive emitron tomography (PET) Nowadays, Octreoscan can be replaced by Gallium-68 DOTA octreotide PET, which has higher sensitivity and specificity.1 However this method is less available. FDG (18F 6-fluordopamine) PET is helpful for staging high grade/poorly differentiated tumors that do not express somatostatin receptors.3 Octeoscan and PET should be used for staging if residual or metastatic disease is suspected.5
5.6. Biochemical markers Serum Chromagranin A is a useful marker in many neuroendocrine tumors but of limited use in non-metastatic rectal NETS.3 It can be useful for monitoring patients with metastatic disease or for surveillance in patients with resected stage II and III tumors.9 Urinary 5hydroxyindoleacetic acid is of little use as few tumors produce serotonin.3
5.7. Treatment Tumor size is the most important predictor of tumor behavior, and although other characteristics are taken into account, this is the main determinant in selecting the treatment option.5,9 Lesions
www.elsevier.pt/ge
REVIEW ARTICLE
Neuroendocrine Rectal Tumors: Main Features and Management ¸as, Isabel Pedroto Ângela Rodrigues ∗ , Fernando Castro-Poc Gastroenterology Department, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal Received 24 March 2015; accepted 29 April 2015 Available online 2 July 2015
KEYWORDS Neuroendocrine Tumors; Rectal Neoplasms
PALAVRAS-CHAVE Tumores Neuroendócrinos; Neoplasias do Reto
∗
Abstract The incidence of neuroendocrine tumors of the rectum has been increasing in the last decades, partly due to improved investigation. They are mostly well-differentiated small tumors with a rather good overall prognosis. In the last few years, some aspects of neuroendocrine tumors have been evolving. In 2010, the World Health Organization proposed a new classification, indicating that these tumors, as a category, should be considered malignant. Afterwards the European Neuroendocrine Tumor Society published their guidelines for the management of colorectal neoplasms. Treatment algorithm is mainly based on tumor size and grading and, in general, well-differentiated rectal tumors 20%
a
Per 10 high-power fields.
neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma. NETs are well-differentiated neuroendocrine neoplasms, with low cellular atypia and proliferative activity and comprises grade G1 or G2 tumors. NECs are a poorly differentiated neuroendocrine neoplasm, showing marked cellular atypia and high proliferative activity. NECs are grade G3 tumors and two categories are recognized: large cell NEC and small cell NEC.4,5 Jernman et al6 demonstrated that this new WHO classification predicted the metastatic potentional of rectal NETs better than the previous 2000 classification, since G1 NETs had an indolent clinical course and G2 NETs often metastasize. Yamaguchi et al7 also concluded that the classification of gastrointestinal NETs into G1 and G2 based on Ki-67 index was appropriated to predict metastases and recurrences; for Salama et al8 Ki-67 appears as a reliable and reproducible marker for the grading of NETs and more superior than mitotic rate. The American Joint Cancer Commission published, in 2010, a tumor---node---metastasis (TNM) classification system for colorectal NETs similar to the one previous proposed by the European Neuroendocrine Tumor Society (Table 2).9 In order to assess the relevance of the TNM classification system, Jann et al10 conducted a retrospective study with midgut and hindgut NETs that confirmed the prognostic relevance and applicability of the classification. In 2012, the European Neuroendocrine Tumor Society (ENETS) released guidelines for the management of patients with colorectal neuroendocrine neoplasms, to reflect the new relevant data on this matter, including the WHO classification.5
3. Epidemiology Data from the Surveillance, Epidemiology and End Results (SEER) suggests that the incidence of rectal NETs have been increasing over the last decades; rectal NETs represented 29% of all GEP-NETs in the latest report, establishing the rectum as the most common location, slightly above the small intestine.11 In Europe, as indicated by an English12 and an Austrian13 studies, the rectum was the fifth and fourth most common location with a frequency of 8% and 14%, respectively. In Asia, rectal NETs take on special relevance, representing 56% of all GEP-NETs in Ito et al14 study. In Modlin et al15 report, rectal NETs also appear to
Neuroendocrine Rectal Tumors
215
Table 2 American Joint Cancer Commission 2010 TNM classification. T (primary tumor) Tx Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor invades lamina propria or submucosa and size ≤2 cm T1a Tumor size 2 cm with invasion of lamina propria or submucosa T3 Tumor invades through muscular propria into subserosa or into nonperitonealized pericolic or perirectal tissue T4 Tumor invades peritoneum or other organs N (Regional Lymph nodes) Nx Regional lymph nodes cannot be assessed N1 No regional lymph node metastases N2 Regional lymph node metastases M (Distant metastases) M0 No distant metastases M1 Distant metastases Stage I IIA IIB IIIA IIIB IV
T1N0M0 T2N0M0 T3N0M0 T4N0M0 AnyTN1M0 AnyTAnyNM1
be over-represented among the Asian populations within the United States. These data suggests that there are likely genetic pre-disposing factors, although some differences may also be attributable to higher colonoscopy screening rates and better reporting of polyps removed at endoscopy.3 Rectal NETs may have a slight male preponderance16,17 and the diagnosis is usually made in the sixth decade of life.16---18
Figure 1
Submucosal tumor in the middle rectum.
Lymph node and distant metastasis are found in about 8% and 4% of patients, respectively.20 Rectal NETs have a good overall prognosis with a 5-year survival rate of 75.2---88.3%.15 Disease stage is the main prognostic factor of rectal NETs. The 5-year overall survival rates reported are 94---100, 54---74 and 15---37% for patients with localized, nodal positive and metastatic rectal NETs, respectively.23 Risk factors for metastatic disease include tumor size, muscularis propria invasion, proliferation index, lymphovascular and perineural invasion.5,20,23 Yoon et al.16 described distant metastasis rates for tumors ≤1 cm, >1 to ≤2 cm, and >2 cm of 1.7, 15 and 50%, respectively. Weinstock et al22 reported 5-years survival rates of 87.7, 47.6 and 33.3% for patients with G1, G2 e G3 tumors, respectively.
5. Diagnosis and staging 5.1. Colonoscopy
4. Clinical characteristics, prognosis Most patients are asymptomatic and diagnosis is made upon routine lower endoscopy or for investigation of unrelated symptoms. In symptomatic patients, the most frequent symptoms are rectal bleeding, pain, constipation and tenesmus.3,16 Carcinoid syndrome is very rare as the tumors themselves rarely produce serotonin.5 The majority of rectal NETs are small size lesions; in a recent systematic review 79% of tumors were less than 1 cm and only 5% were greater than 2 cm.19 Kasuga et al20 reported a mean tumor size of 7.1 mm in their series. Most lesions are found in the midrectum as suggested by Kim et al21 study, in which 74.8% of tumors were found between 5 and 9.9 cm of the anal verge. Most rectal NETs (89%) are limited to the submucosa layer20 and are low grade tumors; Weinstock et al22 reported that G1 tumors accounted for 88.1, G2 for 8.2 and G3 for 3.5% of rectal neoplasms in their series.
Rectal NETs appear usually as small, sessile, submucosal tumors covered with yellow discolored mucosa.19 Atypical endoscopic features such as unusual tumor shape (semipedunculated and ulcerofungating), color (hyperemia) and surface change (depression, erosion, and ulceration) can be associated with metastasis.21 A full colonoscopy is recommended to exclude concomitant colonic disease and the possibility of synchronous carcinoma5 (Figs. 1 and 2).
5.2. Rectal ultrasound Rectal ultrasound (RUS) can accurately assess tumor size, depth of invasion and presence of pararectal lymph node metastases, which is particularly important to determine the adequate treatment modality.5 Kobayashi et al performed ultrasonographic evaluation with echocolonoscopes in 21 lesions and ultrasonic probes in 32 lesions. Rectal
216
Figure 2
Â. Rodrigues et al.
Submucosal tumor with yellow discolored mucosa.
NETs appeared as well-demarcated, homogenous, isoechoic or hypoechoic lesions and the depth of invasion was correctly identified in all lesions (submucosal in 49/52 lesions). RUS could accurately diagnose the invasion depth of lesions as small as 2 mm in diameter.24 High frequency ultrasound probes proved to be especially useful in assessing invasion of small lesions limited to the mucosa or submucosa25 and therefore can be particularly adequate for evaluating the depth of invasion in neuroendocrine rectal tumors. Another two studies found an accuracy of 91 and 100% for determination of tumor invasion with RUS.26,27 According to ENETS recommendation RUS should be performed prior to treatment to determine tumor invasion5 (Figs. 3 and 4).
Figure 4
Hypoechoic lesion on the submucosal layer.
5.3. Computed tomography and magnetic resonance In rectal NETs, the role of computed tomography (CT) is not to detect the primary tumor nor to appreciate its invasion of the rectal wall, but to detect regional and distant metastases. CT has a reported mean detection rate for liver metastasis in neuroendocrine tumors of 81%. The CT appearance of NET lymph node metastases is similar to those from other malignant tumors, although a marked contrast enhancement is frequent.2 Magnetic resonance imaging (MRI) is superior for determining liver metastases and can be used where there is uncertainty over the nature of lesions identified on CT.3,5 The ENETS consensus recommend CT/MRI for patients with tumors >10 mm in size and when residual and metastatic disease is suspected.5 In the NANETS guidelines it is stated that for tumors smaller than 2 cm and confined to the mucosa or submucosa, these studies are not routinely recommended.9
5.4. Scintigraphic scanning (Octreoscan)
Figure 3
Hypoechoic lesion on the muscularis mucosa layer.
Radiolabelled somatostatin analogs are used to detect somatostatin receptor positive tissue. The detection of primary tumor in the rectum NETs can be difficult because of greater background activity. In addition, some tumors may not express somatostatin receptors, particularly higher grade NETS, and so the presence of metastatic disease is better evaluated by other methods such as CT. In the presence of metastatic disease, this method can be useful to determine somatostatin receptor expression which may have impact in selecting some therapies.3,5
Neuroendocrine Rectal Tumors
5.5. Positive emitron tomography (PET) Nowadays, Octreoscan can be replaced by Gallium-68 DOTA octreotide PET, which has higher sensitivity and specificity.1 However this method is less available. FDG (18F 6-fluordopamine) PET is helpful for staging high grade/poorly differentiated tumors that do not express somatostatin receptors.3 Octeoscan and PET should be used for staging if residual or metastatic disease is suspected.5
5.6. Biochemical markers Serum Chromagranin A is a useful marker in many neuroendocrine tumors but of limited use in non-metastatic rectal NETS.3 It can be useful for monitoring patients with metastatic disease or for surveillance in patients with resected stage II and III tumors.9 Urinary 5hydroxyindoleacetic acid is of little use as few tumors produce serotonin.3
5.7. Treatment Tumor size is the most important predictor of tumor behavior, and although other characteristics are taken into account, this is the main determinant in selecting the treatment option.5,9 Lesions
